Vitamin C boosts DNA demethylation in TET2 germline mutation carriers
Abstract Background Accurate regulation of DNA methylation is necessary for normal cells to differentiate, develop and function. TET2 catalyzes stepwise DNA demethylation in hematopoietic cells. Mutations in the TET2 gene predispose to hematological malignancies by causing DNA methylation overload a...
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| Format: | Article |
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BMC
2023-01-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-022-01404-6 |
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| author | Aurora Taira Kimmo Palin Anna Kuosmanen Niko Välimäki Outi Kuittinen Outi Kuismin Eevi Kaasinen Kristiina Rajamäki Lauri A. Aaltonen |
| author_facet | Aurora Taira Kimmo Palin Anna Kuosmanen Niko Välimäki Outi Kuittinen Outi Kuismin Eevi Kaasinen Kristiina Rajamäki Lauri A. Aaltonen |
| author_sort | Aurora Taira |
| collection | DOAJ |
| description | Abstract Background Accurate regulation of DNA methylation is necessary for normal cells to differentiate, develop and function. TET2 catalyzes stepwise DNA demethylation in hematopoietic cells. Mutations in the TET2 gene predispose to hematological malignancies by causing DNA methylation overload and aberrant epigenomic landscape. Studies on mice and cell lines show that the function of TET2 is boosted by vitamin C. Thus, by strengthening the demethylation activity of TET2, vitamin C could play a role in the prevention of hematological malignancies in individuals with TET2 dysfunction. We recently identified a family with lymphoma predisposition where a heterozygous truncating germline mutation in TET2 segregated with nodular lymphocyte-predominant Hodgkin lymphoma. The mutation carriers displayed a hypermethylation pattern that was absent in the family members without the mutation. Methods In a clinical trial of 1 year, we investigated the effects of oral 1 g/day vitamin C supplementation on DNA methylation by analyzing genome-wide DNA methylation and gene expression patterns from the family members. Results We show that vitamin C reinforces the DNA demethylation cascade, reduces the proportion of hypermethylated loci and diminishes gene expression differences between TET2 mutation carriers and control individuals. Conclusions These results suggest that vitamin C supplementation increases DNA methylation turnover and provide a basis for further work to examine the potential benefits of vitamin C supplementation in individuals with germline and somatic TET2 mutations. Trial registration: This trial was registered at EudraCT with reference number of 2018-000155-41 (01.04.2019). Graphical Abstract |
| first_indexed | 2024-04-10T22:47:39Z |
| format | Article |
| id | doaj.art-e9a7e3b89fd54829af3b590f0b2a106b |
| institution | Directory Open Access Journal |
| issn | 1868-7083 |
| language | English |
| last_indexed | 2024-04-10T22:47:39Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj.art-e9a7e3b89fd54829af3b590f0b2a106b2023-01-15T12:14:55ZengBMCClinical Epigenetics1868-70832023-01-0115111310.1186/s13148-022-01404-6Vitamin C boosts DNA demethylation in TET2 germline mutation carriersAurora Taira0Kimmo Palin1Anna Kuosmanen2Niko Välimäki3Outi Kuittinen4Outi Kuismin5Eevi Kaasinen6Kristiina Rajamäki7Lauri A. Aaltonen8Department of Medical and Clinical Genetics, University of HelsinkiDepartment of Medical and Clinical Genetics, University of HelsinkiDepartment of Medical and Clinical Genetics, University of HelsinkiDepartment of Medical and Clinical Genetics, University of HelsinkiDepartment of Clinical Medicine, Faculty of Health Sciences, University of Eastern FinlandPEDEGO Research Unit, University of OuluDepartment of Medical and Clinical Genetics, University of HelsinkiDepartment of Medical and Clinical Genetics, University of HelsinkiDepartment of Medical and Clinical Genetics, University of HelsinkiAbstract Background Accurate regulation of DNA methylation is necessary for normal cells to differentiate, develop and function. TET2 catalyzes stepwise DNA demethylation in hematopoietic cells. Mutations in the TET2 gene predispose to hematological malignancies by causing DNA methylation overload and aberrant epigenomic landscape. Studies on mice and cell lines show that the function of TET2 is boosted by vitamin C. Thus, by strengthening the demethylation activity of TET2, vitamin C could play a role in the prevention of hematological malignancies in individuals with TET2 dysfunction. We recently identified a family with lymphoma predisposition where a heterozygous truncating germline mutation in TET2 segregated with nodular lymphocyte-predominant Hodgkin lymphoma. The mutation carriers displayed a hypermethylation pattern that was absent in the family members without the mutation. Methods In a clinical trial of 1 year, we investigated the effects of oral 1 g/day vitamin C supplementation on DNA methylation by analyzing genome-wide DNA methylation and gene expression patterns from the family members. Results We show that vitamin C reinforces the DNA demethylation cascade, reduces the proportion of hypermethylated loci and diminishes gene expression differences between TET2 mutation carriers and control individuals. Conclusions These results suggest that vitamin C supplementation increases DNA methylation turnover and provide a basis for further work to examine the potential benefits of vitamin C supplementation in individuals with germline and somatic TET2 mutations. Trial registration: This trial was registered at EudraCT with reference number of 2018-000155-41 (01.04.2019). Graphical Abstracthttps://doi.org/10.1186/s13148-022-01404-6DNA methylationTET2 mutationsVitamin CHematological neoplasia |
| spellingShingle | Aurora Taira Kimmo Palin Anna Kuosmanen Niko Välimäki Outi Kuittinen Outi Kuismin Eevi Kaasinen Kristiina Rajamäki Lauri A. Aaltonen Vitamin C boosts DNA demethylation in TET2 germline mutation carriers Clinical Epigenetics DNA methylation TET2 mutations Vitamin C Hematological neoplasia |
| title | Vitamin C boosts DNA demethylation in TET2 germline mutation carriers |
| title_full | Vitamin C boosts DNA demethylation in TET2 germline mutation carriers |
| title_fullStr | Vitamin C boosts DNA demethylation in TET2 germline mutation carriers |
| title_full_unstemmed | Vitamin C boosts DNA demethylation in TET2 germline mutation carriers |
| title_short | Vitamin C boosts DNA demethylation in TET2 germline mutation carriers |
| title_sort | vitamin c boosts dna demethylation in tet2 germline mutation carriers |
| topic | DNA methylation TET2 mutations Vitamin C Hematological neoplasia |
| url | https://doi.org/10.1186/s13148-022-01404-6 |
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